p40 homodimers bridge ischemic tissue inflammation and heterologous alloimmunity in mice via IL-15 transpresentation
Hidetoshi Tsuda, Karen S. Keslar, William M. Baldwin III, Peter S. Heeger, Anna Valujskikh, Robert L. Fairchild
Hidetoshi Tsuda, Karen S. Keslar, William M. Baldwin III, Peter S. Heeger, Anna Valujskikh, Robert L. Fairchild
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Research Article

p40 homodimers bridge ischemic tissue inflammation and heterologous alloimmunity in mice via IL-15 transpresentation

Abstract

Virus-induced memory T cells often express functional cross-reactivity, or heterologous immunity, to other viruses and to allogeneic MHC molecules that is an important component of pathogenic responses to allogeneic transplants. During immune responses, antigen-reactive naive and central memory T cells proliferate in secondary lymphoid organs to achieve sufficient cell numbers to effectively respond, whereas effector memory T cell proliferation occurs directly within the peripheral inflammatory microenvironment. Mechanisms driving heterologous memory T cell proliferation and effector function expression within peripheral tissues remain poorly understood. Here, we dissected proliferation of heterologous donor-reactive memory CD8+ T cells and their effector functions following infiltration into heart allografts with low or high intensities of ischemic inflammation. Proliferation within both ischemic conditions required p40 homodimer–induced IL-15 transpresentation by graft DCs, but expression of effector functions mediating acute allograft injury occurred only in high-ischemic allografts. Transcriptional responses of heterologous donor-reactive memory CD8+ T cells were distinct from donor antigen–primed memory CD8+ T cells during early activation in allografts and at graft rejection. Overall, the results provide insights into mechanisms driving heterologous effector memory CD8+ T cell proliferation and the separation between proliferation and effector function that is dependent on the intensity of inflammation within the tissue microenvironment.

Authors

Hidetoshi Tsuda, Karen S. Keslar, William M. Baldwin III, Peter S. Heeger, Anna Valujskikh, Robert L. Fairchild

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Figure 3

p40HD-induced IL-15 production and endogenous memory CD8+ T cell proliferation in allografts subjected to minimal CIS are obviated by graft CD11c+ cell depletion.

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p40HD-induced IL-15 production and endogenous memory CD8+ T cell prolife...
(A) Groups of A/J mice (n = 4–5 per group) received cardiac allografts subjected to 0.5 hours of CIS from either C57BL/6 or B6.DTR-CD11c transgenic mice that were treated with or without diphtheria toxin (DT; 40 ng/g body weight) on days –2 and –1 before transplantation. On day 1 after transplant, indicated recipients received 2 μg recombinant p40HDs i.v., and all recipients were injected with 100 μg BrdU i.p. on days 0 and 1. The next day, allografts were harvested and digested, and aliquots of single-cell suspensions were stained with antibody and analyzed by flow cytometry to quantitate the proliferation of memory CD8+ T cells by BrdU incorporation. **P < 0.01 as determined by the Kruskal-Wallis test. (B) Cardiac allografts from wild-type (WT) C57BL/6 or B6.IL12Rβ1–/– mice were subjected to 0.5 hours of CIS and transplanted to groups of BALB/c mice (n = 5–6). Recipients were injected with 100 μg BrdU i.p. on days 0 and 1 after transplant and received PBS or 2 μg recombinant p40HDs i.v. on day 1 after transplant. The next day, allografts were harvested and digested, and aliquots of single-cell suspensions were stained with antibody and analyzed by flow cytometry to quantitate the infiltration and the BrdU incorporation of memory CD8+ T cells. *P < 0.05 as determined by the Mann-Whitney nonparametric test. (C and D) On day 2 after transplant, total protein was purified from harvested grafts of indicated recipients, and IL-15 (C) or IL-15/IL-15R complex (D) levels were tested by ELISA. *P < 0.05, **P < 0.01 as determined by the Kruskal-Wallis test.